Brain tumors are the most common solid tumor and the leading cause of cancer-related death in children. Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Dissemination (metastasis) of MB results in seeding the leptomeningeal membranes that cover the brain and spinal cord. In prior work, we demonstrated that metastases are biologically distinct from their matched primary tumor that metastases are the overwhelming cause of death in children with MB, and that metastatic disease which frequently develops post-therapy is highly clonally divergent to therapy nave metastases. Group 3 medulloblastoma (G3 MB) is responsible for the majority of deaths among MB patients. While only a third of G3 MB patients have visible metastases at diagnosis, almost 100% of patients with recurrent disease have metastases. The major source of morbidity in MB survivors is irradiation of the entire developing brain and spinal cord, performed to prevent metastatic recurrence, but leaving survivors with cognitive delay, growth failure, and secondary cancers. Modest decreases in the dose of craniospinal radiation would significantly improve quality of life for survivors. Understanding the biological basis of leptomeningeal dissemination, progression, and recurrence in G3 MB could therefore allow the development of therapies to supplement craniospinal radiation, enabling radiation dose reductions without an increased rate of recurrence. We have shown previously that, whereas most SHH tumors recur locally, G3 almost always recurs metastatically. This proposal leverages a well-validated GEMM model of G3 MB made collaboratively in the PIs labs, to discover genes that drive up-front metastatic initiation/progression and metastatic recurrence after radiation therapy. Identifying these genes should enable us to test novel therapies in a mouse hospital setting, to prevent metastatic recurrence in the setting of reduced craniospinal radiation. Our aims are to: Aim 1. Discover genes and pathways that initiate and drive progression of up-front metastases in G3 MB utilizing our animal model (functional genomics), followed by validation in human samples (cancer genomics) and functional validation using in vivo mouse models. Aim 2. Discover genes and pathways that initiate and drive progression of post-treatment metastases in G3 MB in response to radiation. We will use functional genomics and cancer genomics in a humanized mouse hospital setting, delivering both microneurosurgery and image guided multifractionated craniospinal radiotherapy. Aim 3. Initiate murine clinical trials to prophylactically prevent metastatic recurrence of G3 MB after surgery and reduced dose craniospinal irradiation, through delivery of novel agents targeting of mTOR, aneuploidy, and additional targets discovered in Aims #1 and #2.